The present invention relates to the field of pharmacology and, more particularly, to the treatment of pain.
Inadequate pain management is widely prevalent and harmful to patients. Numerous studies have demonstrated poor control of post-operative and trauma pain, cancer pain and chronic non-cancer pain. Thus, there is a continuing need for medications able to provide high efficacy pain relief while reducing the possibility of undesirable effects.
Pain can be classified into two main categories, acute and chronic, differing in their etiology, pathophysiology, diagnosis and treatment. Acute pain is nociceptive in nature (i.e. resulting directly from local tissue injury). It is a normal, predictable physiological response to an adverse chemical, thermal, or mechanical stimulus associated with surgery, trauma, or acute illness. It is normally self-limited such that when the condition producing the pain resolves, the pain disappears. Chronic pain may be defined as pain persisting longer than the expected time of tissue healing. Injury or a disease process can trigger chronic pain, but other factors besides the triggering event can perpetuate the pain. Chronic pain may be either neuropathic (i.e. initiated or caused by a primary lesion or dysfunction in the nervous system) or nociceptive.
Nociceptive pain is typically treated with anti-inflammatory or analgesic medications whereas neuropathic pain is usually treated with medications that influence neurotransmitters. These include, for example, antidepressants, and antiepileptic drugs. Patients with refractory neuropathic pain are typically treated with opioids.
One neurotransmitter which is known to be involved in the complex circuitry underlying pain is the inhibitory neurotransmitter, gamma-amino butyric acid (GABA). GABA is not transported efficiently into the brain from the bloodstream because of poor transport properties that prevent passage through the blood-brain barrier. Consequently, brain cells synthesize virtually all of the GABA found in the brain (by decarboxylation of glutamic acid with pyridoxal phosphate).
GABA regulates neuronal excitability through binding to specific membrane proteins (i.e., GABA receptors), which results in opening of an ion channel. The entry of chloride ion through the ion channel leads to hyperpolarization of the recipient cell, which consequently prevents transmission of nerve impulses to other cells.
Although most commonly used for the treatment of anxiety, muscle spasms and epilepsy, GABA agonists have been shown to alleviate the symptoms of pain through a number of mechanisms. For example, pain may be reduced by potentiating GABA transmission. This may involve targeting GABA transporters as well as GABA associated enzymes and receptors, such as the GABA-B receptors [Frediani F. Neurol Sci. 2004, Suppl 3:S161-6]. In addition, GABA agonists may alleviate pain by reducing glutamate-mediated excitatory transmission and/or blocking voltage-activated ion channels. The latter mechanism of action is exemplified by the newer generation of antiepileptics such as lamotrigine and gabapentin in the clinical treatment of neuropathic pain symptoms [Blackburn-Munro G., et al., Curr Pharm Des. 2005; 11 (23):2961-76].
The use of GABA agonists is limited since they typically include hydrophilic functional groups (e.g., a free carboxylic acid group and a free amino group) and therefore do not readily cross the blood brain barrier (BBB). As such, invasive methods of delivery are required for GABA agonists to have a therapeutic effect. However, it was found that chemical conjugation of such compounds with fatty amino acids or peptides could facilitate to some extent their passage across the BBB [Toth I. J. Drug Target 1994, 2, 217-39].
Despite considerable progress in developing new compounds, the use of systemically acting GABA agonists (e.g., gabapentin, pregabalin and various benzodiazepines) is limited by adverse side-effects such as sedation and nausea.
The neurotransmitters norepinephrine and serotonin are functionally inhibitory on pain transmission. Thus, as mentioned hereinabove, monoamine up-regulators such as antidepressants and antiepileptics are also used in the clinical management of pain.
Tricyclic antidepressants are thought to affect pain transmission in the spinal cord by inhibiting the reuptake of norepinephrine and serotonin, both of which influence descending pain pathways. In addition, histamine H1-receptor affinity (associated with sedation) may be correlated with the analgesic effect of antidepressants.
Tricyclic antidepressants may be categorized as secondary or tertiary amines. Secondary amines such as nortriptyline (Pamelor) and desipramine (Norpramin) show relatively selective inhibition of norepinephrine reuptake. Tertiary amines such as amitriptyline and imipramine (Tofranil) exhibit a more balanced inhibition of norepinephrine and serotonin, however, they also have greater anticholinergic side effects. The novel antidepressants venlafaxine (Effexor) and duloxetine (Cymbalta) comprise a balanced inhibition of serotonin and norepinephrine reuptake without blockade of other neuroreceptors that are responsible for typical tricyclic side effects. The mechanism of action of bupropion (Wellbutrin) is uncertain but involves blockade of dopamine uptake.
The efficacy of antidepressant drugs varies dramatically for neuropathic and non-neuropathic pain syndromes. In addition, specific agents within each medication class can vary in effectiveness.
For example, antidepressants with mixed-receptor or noradrenergic activity appear to have the greatest therapeutic effect in patients with neuropathic pain. Predominantly serotoninergic drugs, such as selective serotonin reuptake inhibitors (SSRIs), are ineffective in treating chronic pain [McQuay H J, et al., Pain 1996; 68:217-27]. Amitriptyline and its metabolite nortriptyline have the best documented efficacy in the treatment of neuropathic and non-neuropathic pain syndromes [Bryson H M, Wilde M I. Drugs Aging 1996; 8:459-76]. The novel antidepressants bupropion, venlafaxine and duloxetine [Wernicke J, et al., J Pain 2004; 5 (3 suppl 1):S48] have been proven effective in patients with neuropathic pain.
The efficacy of tricyclic antidepressants in the treatment of neuropathic pain appears to be independent of their antidepressant effect and patients with pain but no depression respond to these agents [Max M B, et al., Neurology 1987; 37:589-96]. Although pain reduction occurs at dosages lower than those typically required to treat depression, therapeutic doses are still associated with a number of side effects including drowsiness, dry mouth, blurred vision, constipation, weight gain, low blood pressure after getting up, urinary problems, headaches, impotence, loss of libido, tremor, dizziness, agitation and insomnia.
U.S. Patent Application No. 20040242570 and International PCT Patent Applications WO 03/026563 and WO 2005/092392, which are incorporated by reference as if fully set forth herein, teach conjugates of psychotropic drugs and GABA, for treating psychotropic disorders, proliferative disorders and for enhancing chemosensitization.